Pyridylethylated 4 (1h)-quinazolinones and derivatives thereof



3,265,696 PYRlDYLETHYLATED 4 (lH)-QUINAZOLINONES AND DERIVATIVES THEREOF Edgar S. Schipper, Clifton, N..l., assignor to Shulton, Inc.,

Clifton, N..l., a corporation of New Jersey No Drawing. Filed July 2, 1964, Ser. No. 380,060 7 Claims. (Cl. 260--256.4)

( orncrnry /NTRI N in which Py is pyridyl; R is either hydrogen or lower alkyl and R R R and R which may be the same or different, are hydrogen, lower alkoxy or halogens, such as bromine or chlorine, Examples of lower alkyl are those containing less than 6 carbon atoms, such as methyl, and examples of lower alkoxy are those containing less than 6 carbon atoms, such as methoxy.

The compounds of this invention manifest central nervous system depressant activity in animals at dosages from 10 to 300 mg. per kg. of body weight. Such dosages are significantly lower than the respective LD of such compounds.

The new pyridylethylated 4(lH)-quinazolinones of this invention may be produced by reacting a substituted 2-B- pyridylethylaminobenzamide with an excess of ethylorothoformate in accordance with the following reaction:

R5 (FI'IEGIIFPY N R r u a iii ates Patent of a 2-B-(4-pyridyl)cthylbenzamide, as typified by the following reaction:

NlI'C1I2C llz- ES 0H0 CONtn l0 ClIsCH2- \N (30cm -N-omc1n H2O -cn l i it O0NIl'z A \/\H/ Non-toxic salts of the pyridylcthylated 4(ll-l)-quinazolinones of this invention are produced by mixing equimolecular amounts of the required pyridylethylated 4(lH)-quinazolinoncs and the required acid in an inert solvent such as ether, ethanol, benzene or toluene, and subsequently filtering the precipitated salts or evaporating the solvent and recovering the solid residue. Salts of inorganic acids such as hydrochloric, sulfuric or phosphoric acids or salts of organic acids such as acetic, succinic, tartaric or ascorbic acid of the pyridylethylated 4(1H)- quinazolinones may be produced in this manner.

A more comprehensive understanding of this invention 3 is obtained by reference to the following examples:

Examples 1-5 2-pyridyl)cth l-4(lH)-quina2ol inone; (4-pyridyl)ethyl-4( l H )-quinazolinone; (4pyridyl)ethyl-6-chloro-4(1H)-quinazol-incne; (4-pyridyl)cthyl-7-chloro4(l H)-quinazolin("ne; (4-pyridyl)ethyl-5-mcthoxy-4(lll)-quinazolinone.

1. g- LB- 1-13- Each of the above pyridylethylated 4(lH)-quina7.olinones was prepared by reacting a solution of 0.1 M of the anthranilamide required and denoted in the following Table I, with 500 ml. of ethylorthoformate. The reaction mixture was refluxed for 12-48 hours. The solution was condensed to half-volume and upon cooling the solid product precipitated and was collected by filtration. For

final purification, it was recrystallized from the solvent indicated in Table II.

TABLE I Pyridylethylatcd 4(1ll)-quin- Anthrnnilamide intermediate ample d azolinone produced use 2 1-p-(4'pyridyl)ethyl-4(11I)- quinazuliuone.

4 1-13-(4-pyridyl)cthyl-7-chloro-4 (1I-l)-quinuzolin0ne.

5 1-5-(4-pyri lyi)cthyl-5- metltoxy-4(1ll)-quinazolinone.

2 3-(2m'ridyDethyl-aminollfillZtlllildG. 2-5-(l-pyridyDethyl-tnniuohQl'lZttltlldO. Z-fl-(t-pyridyDethyl-mnino-fichlorobenzamide. 2-5-(44tyridyDethyl-amino-L chlorohenzainide. 2-5(4-pyridyDethyl-antino-G- methoxybeuzainide.

The following table shows the solvent which was used in the recrystallization of the l-pyridylethylated 4(lH)- At the lower inlraperitoneal dosage level tested of .mg./kg. of body weight, the 1-,B-(4-pyridyl)ethyl-4-(lH)- quinazolinone significantly prolonged hexobarbital sleeping time.

of the examples. 5 The results of this study indicate that the compound of TABLE II Analysis Solvent Used in Rccrys- Yield, Example talizatiou M.P., C. Calculated Found Percent o H N O H N Ethyl acctate/ethanol 174-175 71. 70 5. 21 16.72 71. 52 5.44 16.47 2 ..d 71.70 5.21 16.72 71.77 5.25 16.72 07 Methanol 63. 05 4.23 14.71 62.79 4.20 14. 60 as Ethyl acetate" 63. 05 4. 23 14.71 62. 75 4.50 14.54 48 .d 67.68 5. 37 14. 94 07. 90 5.45 14. 87 28 Example 6.--1-[3-(4-pyridyl)ethyl-2-methyl-4(1H)- this invention tested significantly prolonged hexobarbital quinazolz'none sleeping time.

1- TABLE III.-'1HE EFFECTS oF PRE'IREATMENT wr'rtr 0.334.:'ifi ii fl iiiiii ziiii oi iiitfiiiiifiih negatingas;newsman ON dropwise to an ice-cold and stirred solution of 500 ml. of pyridine- A Solution of 50 gof 'I 'Py y y Mean Sleeping TirneiS. D. (Minutes) benzamide in 500 ml. of pyridine was added over a 15 1305888153791 (mg-l minute interval keeping the temperature below 10 C. by pretreated Controls means of an ice bath. The reaction mixture was stirred 30 at 10 C. for one hour and the solvent was evaporated 100 6 333* under reduced pressure. The residue was dissolved in 10 0517 49$! 200 ml. of 10% hydrochloric acid. The solution was H b m i m 100 t l n d i t 1 0 e o o I 1 ties. 142231212722 estatesmarter. ats. 1a..thas?am:sat I: I c water, dried, heated at 135 C. for 20 minutes and finally What 1s claimed is: recrystallized with ethyl acetate to give 40 g. (73%) yield A compound selected from the class consist ng of of the desired product. The meltingpoint of the 1-19-(4- pyrlfiylethylated )-q l and n-t xic acid pyridyl)ethyl 2- methyl-4(lH)-quinazolinones was 159- addliloll Salts ilhcffiof, 531d Py y y )-q 160 C. Analysis showed it to contain 72.72% carbon, 40 azohnones havms the ula: 5.72% hydrogen and 15.87% nitrogen compared with H theoretical quantities of 72.43% carbon, 5.70% hydrogen ZCHPY and 15.88% nitrogen. /N

Pharmacological tests were conducted to ascertain the T effect of a compound of this invention in the prolonga- R N tion action of hexobarbital. For this purpose 1-{3-(4- pyridyl)ethyl-4(lH)-quinazolinone of Example 2 was sel ll lected for this study. The procedure of the testing was as follows: in which Py is selected from the group consisting of g male SW15: i d t 3 to h%-) 1 2-pyr1dyl and 4-pyridyl; R is selected from the group v1 e 1n 0 groups 0 on an ase overmg e consistim of h dm en d l l R -py yb y quinazolinone was administered and R a re sele cted fron i the g i iip 531 152231531 iii/21m intraperitoneally at the dosage levels indicated in Table gen lower alkoxy bromine and chlorine 1111 ten minutes prior to the intraperitoneal injection of 1 fl (2 pyl.idy])ethyl 4 (lH) qu.inazolinone 100 ring/kg. of hexobarbital sodium. Control mice re- 1 fl (4 pyridyl)ethyl 4 (lH) quinazolinone: ceived the same dose of hexobarbital sodium without pre- 1 fi (4 pyr;dyl)ethyl 6 chlom 4 (1H) quinaZO1inone treatment. The interval between the loss and spontaneous 5, 1 p-(4-pyridyl)ethyl-7-ChlOrO-4-(lH)-quina20lin0nc return of the righting reflex (sleeping time) was recorded 1 fi (4 pyridy1)cthyl 5 methoxy 4 (lHyquinazolim for each animal and mean sleeping times for treated and control groups were compared statistically. 7 1- 4- rid .1 1-2- {h Solutions of the test material were prepared daily by W y) y me yl 4 (1H) qumazolmonc' dissolving the weighed amount of the sample in a minimal References Cited by the Examiner amount of 1.0 N HCl and diluting to final volume with saline. The concentration of the test solutions was 10 chakralfartl et Expenentla 9, 1953, P mgjmL Pakrashi et al., Tetrahedron, vol. 19, 1963, pages The results of this study are summarized in Table III. These results show that 1-B-(4-pyridyl)ethyl-4(1H)-quinazolinone markedly prolonged hexobarbital sleeping time at the mg./kg. dosage level.

HENRY R. JILES, Acting Primary Examiner. MARY U. OBRIEN, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF PYRIDYLETHYLATED 4-(1H)-QUINAZOLINONES AND NON-TOXIC ACID ADDITION SALTS THEREOF, SAID PYRIDYLETHYLATED 4-(1H)-QUINAZOLINONES HAVING THE FORMULA: 